A central problem in approaches to cancer immunotherapy has been the lack of animal models to aid the study of cancer patients' immune response to their tumors. Our major goal is to develop an animal model in which the immune responses of cancer patients' lymphocytes can be both characterized and manipulated. Mice with severe combined immunodeficiency (SCID) may provide such a model. Whereas secondary B-cell responses have been elicited in SCID mice, the suitability of this animal model for the study of T-cell responses has yet to be demonstrated. This issue is of importance in light of the postulated regulatory role of T cells in the control of cancer. Our preliminary data in this animal model demonstrate that SCID mice can be reconstituted with a functional human B lymphoid system and also allow growth of both primary and metastatic melanoma. Growth of metastatic lesions is inversely correlated with the presence of circulating human antibody in the mice suggesting a protective role of tumor-infiltrating lymphocytes (TIL). Based on these preliminary data we propose to characterize patients' TIL responses in SCID mice. The determined and functional activities of the TIL (cytolytic T lymphocytes, and lymphokine- activated or natural killer cells) will be characterized. To establish a model of active immunotherapy of cancer in SCID mice, we will first optimize reconstitution of the mice with human peripheral blood mononuclear cells (PBMC) using tetanus toxoid as a model antigen. We will then demonstrate that the anti-tumor activity in the B and T cells of cancer patients can be maintained in a functional state in the mice. To demonstrate B-cell functions, we will inject SCID mice with PBMC from melanoma patients who respond to treatment with autologous tumor vaccine by producing anti-melanoma antibodies. Mice will be boosted with tumor vaccine and human antibody production will be determined. To demonstrate T-cell functions, a CTL line which we have recently established against melanoma, will be injected together with IL-2 and inactivated autologous tumor cells into SCID mice. CTL activity of the in vivo-stimulated cells will then be measured in vitro. If these experiments are successful we will examine the potential of the SCID mouse model in the preclinical testing of tumor vaccines. A useful model will enable us to predict the immunogenicity and protective efficacy of the tumor vaccine in cancer patients. SCID the melanoma-associated antigen chondroitin sulfate proteoglycan (CSP) or with inactivated tumor cells known to induce humoral and cellular immunity in cancer patients. If we are able to induce the preclinical screening of potential cancer vaccines to predict their immunogenicity, and, eventually, protective efficacy in patients.